Immunophilins are the cytoplasmic protein targets of immunosuppressive drugs and are divided into two families: the cyclophilins, which bind cyclosporin A (Sandimmune) and related compounds, and the FKBPs, which bind FK506 (Tacrolimus), rapamycin (Sirolimus) and related compounds. Both cyclosporin A and FK506 have been approved for human use to prevent the rejection of transplanted organs. Immunosuppressive compounds could also be used to treat autoimmune diseases such as rheumatoid arthritis and insulin dependent diabetes if less toxic agents were available. Since they control cell cycling, immunosuppressive compounds are also useful as reagents in cell biology and potentially useful as chemotherapeutic agents for cancer. All of these uses require a better understanding of the structures of immunophilin-immunosuppressant complexes.
Specific aims towards this goal include: 1) Structures of FKBP12 complexes that define the binding and effector regions of FK506-like materials and the effector region of rapamycin-like materials. 2) Structures of FKBP12 complexes of FK506-peptide hybrids to characterize a rapidly accessible and highly diverse set of drug candidates. 3) Structures of trimeric complexes of FKBP12-rapamycin-FRAP. Immunophilins are used as modular units to generate larger protein constructs and ligands serve as dimerizing agents to bring these modules together. These immunophilin complexes could be useful as cell cycle arrest agents for cancer chemotherapy and as agents to control gene expression and other cellular processes.
Some specific aims to achieve these goals are: 4) Structures of the FKBP212-dimerizer-FKBP12 triple complexes using first generation dimerizers such as FK1012A, B, and C. 5) Structures of protein-ligand complexes where the partners have been modified in a compensatory fashion (""""""""hole-bump"""""""" complexes). Structures of both FKBP12-FK506 and cyclophilin A-Cyclphilin A complexes will be studied to design two distinctly different families of dimerizing agents with no affinity for wild type immunophilins.
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